Kouzi S A, McMurtry R J, Nelson S D
Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle 98195.
Chem Res Toxicol. 1994 Nov-Dec;7(6):850-6. doi: 10.1021/tx00042a020.
The hepatotoxicity of the herbal plant germander and that of one of its major furanoneoclerodane diterpenes, teucrin A, were investigated in mice. Teucrin A was found to cause the same midzonal hepatic necrosis as observed with extracts of the powedered plant material. Evidence that bioactivation of teucrin A by cytochromes P450 (P450) to a reactive metabolite(s) is required for initiation of the hepatocellular damage is provided by results of experiments on the induction and inhibition of P450 and from studies on the effects of glutathione depletion. Pretreatment of mice with the P450 inducer phenobarbital enhanced the hepatotoxic response, as indicated by an increase in plasma alanine aminotransferase (ALT) levels and hepatic necrosis, while pretreatment with the P450 inhibitor piperonyl butoxide markedly attenuated the toxic response. Hepatotoxicity of teucrin A also was increased following pretreatment with the inhibitor of glutathione synthesis buthionine sulfoximine. Most importantly, the tetrahydrofuran analog of teucrin A, obtained by selective chemical reduction of the furan ring, was not hepatotoxic, a result that provides strong evidence that oxidation of the furan ring moiety of the neoclerodane diterpenes is involved in the initiation of hepatocellular injury caused by germander.
研究了草药植物水苏属及其主要呋喃新克罗烷二萜之一——水苏素A对小鼠的肝毒性。结果发现，水苏素A所导致的肝中叶坏死与粉状植物材料提取物所观察到的相同。细胞色素P450（P450）将水苏素A生物活化成一种或多种反应性代谢物是引发肝细胞损伤所必需的，这一证据来自于P450诱导和抑制实验的结果以及谷胱甘肽耗竭效应的研究。用P450诱导剂苯巴比妥预处理小鼠可增强肝毒性反应，血浆丙氨酸转氨酶（ALT）水平升高和肝坏死增加表明了这一点，而用P450抑制剂胡椒基丁醚预处理则可显著减弱毒性反应。用谷胱甘肽合成抑制剂丁硫氨酸亚砜胺预处理后，水苏素A的肝毒性也增加。最重要的是，通过对呋喃环进行选择性化学还原得到的水苏素A的四氢呋喃类似物没有肝毒性，这一结果有力地证明了新克罗烷二萜的呋喃环部分的氧化参与了水苏属引起的肝细胞损伤的起始过程。
